This invention relates to new 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroids, a process for their production, pharmaceutical preparations that contain these active ingredients as well as their use for the production of pharmaceutical agents, especially for postmenopausal substitution therapy of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
Antigestagenically active steroids are already known from EP 0 057 115 A2. In this connection, this can be 3-oxo-estra-4,9-dienes substituted in 11-position.
11xcex2-Benzaldoximes of the steroid series that have special antigestagenic properties are known from DE 43 32 283 A1, DE 43 32 284 A1, and DE 198 09 845 A1 (WO 9945023 A1).
Described in DE 43 32 283 A1 and DE 43 32 284 A1 are 11xcex2-benzaldoxime-3-oxo-estra-4,9-diene derivatives, which can be substituted according to DE 43 32 283 A1 in 17xcex2-position with hydroxy, alkoxy, acyloxy or aryloxy and in 17xcex1-position with xcfx89-fluoroalkyl.
In DE 198 09 845 A1, substituted 11xcex2-benzaldoxime-3-oxo-estra-4,9-dienes are described. In this case, these are S-substituted carboxylic acid thiol esters of these compounds. The compounds can also be substituted in 17xcex2-position with hydroxy, alkoxy, acyloxy or aryloxy and in 17xcex1-position with xcfx89-fluoroalkyl.
By contrast, steroids with 17xcex1-fluoroalkyl chains are disclosed in DE 197 06 061 A1. These compounds, especially ZK 230211 (11xcex2-(4-acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one): U. Fuhrmann; H. Hess-Stumpp, A. Cleve, G. Neef, W. Schwede, J. Hoffmann, K.-H. Fritzemeier and K. Chwalisz: J. Med. Chem., 2000, 43, 5010-5016), show an almost purely antagonistic activity, high receptor selectivity and, i.a., antiproliferative activity in the tumor models.
The object on which this invention is based consists in finding active ingredients with antigestagenic action that have significantly reduced antiglucocorticoidal action compared to the known compounds and that are suitable for postmenopausal substitution therapy or for treatment of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
Another object on which this invention is based consists in finding a process for the production of active ingredients.
In addition, an object exists in finding pharmaceutical preparations that contain the active ingredients.
The compounds according to the invention have general formula I: 
in which
R1 stands for hydrogen, C1- to C6-alkyl, COR4, COOR4, COSR4 or CONHR5, in which R4 is C1- to C6-alkyl or unsubstituted or substituted aryl, and in which R5 is hydrogen, C1- to C6-alkyl or unsubstituted or substituted aryl,
R2 stands for hydrogen, C1- to C6-alkyl or C1- to C6-acyl, and
R3 stands for a CnF2n+1 group, in which n=1, 2 or 3, or for a CH2O(CH2)mCnF2n+1 group, in which m=0 or 1 and n=1, 2 or 3.
In all other positions of the steroid skeleton as well as on the phenylene radical in 11xcex2-position, any other substituents, especially alkyl and aryl groups, can be bonded instead of hydrogen. In addition, this invention relates to pharmaceutically compatible salts of these compounds. Such acid addition salts can be salts of inorganic and organic acids, for example salts of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other usable acids are described in, for example: Fortschritte der Arzneimittelforschung [Progress in Pharmaceutical Agent Research], Vol. 10, pages 224-225, Birkhxc3xa4user Verlag, Basel and Stuttgart, 1966 as well as in: Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977).
Radicals R1 that are mentioned in this invention are especially a hydrogen atom or a methyl group or acyl groups, such as, for example, formyl, acetyl, propionyl and benzoyl radicals, or carboxylic acid ester groups, for example methoxycarbonyl radicals or ethoxycarbonyl radicals, or carboxylic acid thiol ester groups, such as methylthiocarbonyl radicals or ethylthiocarbonyl radicals, or urethane groups, such as ethylaminocarbonyl radicals or unsubstituted or substituted phenylaminocarbonyl radicals. The substituted phenylaminocarbonyl radical is preferably substituted with a C1- to C6-perfluoroalkyl radical.
R2 preferably stands for a hydrogen atom, a methyl group or an acetyl group.
R3 stands in particular for a perfluoroalkyl with n=1, 2 or 3. R3 can thus stand for 1,1,1-trifluoromethyl, 1,1,2,2,2-pentafluoroethyl or 1,1,2,2,3,3,3-heptafluoropropyl. In addition, R3 can stand for 1,1,1-trifluoroethyloxymethyl, if R3 is provided by general formula CH2O(CH2)mCnF2n+1, and in this case, m=1 and n=1.
The compounds according to the invention are especially the following 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroids:
1) 4-[17xcex2-Hydroxy-17xcex1-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
2) 4-[17xcex2-Hydroxy-17xcex1-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(Z)-oxime
3) 4-[17xcex2-Hydroxy-17xcex1-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
4) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
5) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-O-acetyloxime
6) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
7) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylthio)carbonyl]oxime
8) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethoxy)carbonyl]oxime
9) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(methoxy)carbonyl]oxime
10) 4-[17xcex2-Hydroxy-17xcex1-(1,1,2,2,3,3,3-heptafluoropropyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
11) 4-[17xcex2-Methoxy-17xcex1-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
12) 4-[17xcex2-Methoxy-17xcex1-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
13) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
14) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-O-acetyloxime
15) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
16) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-{O-[(4xe2x80x2-trifluoromethyloxy)phenylamino]carbonyl}oxime
17) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethoxy)carbonyl]oxime
18) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(methoxy)carbonyl]oxime
19) 4-[17xcex2-Methoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylthio)carbonyl]oxime
20) 4-[17xcex2-Acetoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
21) 4-[17xcex2-Acetoxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
22) 4-[17xcex2-Hydroxy-17xcex1-[(1,1,1-trifluoroethyloxy)methyl]-3-oxoestra-4,9-dien-11xcex2-yl]benzaldehyde-1(E)-oxime
In the prior art documents, the 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroids and ester, thiol ester or urethane derivatives thereof are not disclosed. The compounds according to the invention are therefore new and not previously known from the literature. The biological profile of action of the above-mentioned compounds is not described. It is not possible to cover all potential applications with an xe2x80x9cantigestagenxe2x80x9d (W. Elger, K. Chwalisz, Reproduktionsmedizin [Reproduction Medicine], 1999, 15, 318-335; I. M. Spitz, H. J. Bennink: Steroids, 2000, 65 837-838). The compounds according to the invention are suitable for postmenopausal substitution therapy, also in combination with an estrogen, or can be used for treatment of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
This invention also relates to a production process for the 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroids according to the invention.
The 17xcex1-fluoroalkyl groups can be introduced into the steroid skeleton by a 17-ketone being used as a starting material according to methods that are known in the art. Ruppert had described the production of trifluoromethyltrimethylsilane (Tetrahedron Letters, 1984, 25, 2195), which is highly suitable for the introduction of the trifluoromethyl group from aldehydes and ketones in the presence of tetrabutylammonium fluoride. (R. Krishnamurti, D. R. Bellew, G. K. S. Prakash, J. Org. Chem., 1991, 56, 984 and Lamberth, J. Prakt. Chem., 1996, 338, 586-587, Ruppert""s Reagent).
To introduce the homologous fluoroalkyl groups into the steroid skeleton, 17-ketones can be used as a starting material. To this end, processes were described in which fluoroalkyl compounds with the general formula halogen-CnF2n+1 are reacted in situ with metal to form organometallic compounds of the alkali or alkaline-earth series with the general formula metal-CnF2n+1. The latter can then be reacted with the 17-ketones to form 17 xcex1-fluoroalkyl-17xcex2-hydroxy compounds. (DE 197 06 061 A1). The 17xcex1-fluoroalkoxymethyl grouping can preferably be introduced by a ring opening reaction from a corresponding 17(20)-spiroepoxide [Ponsold, Hxc3xcbner, Schnabel, Strecke, Arzneimittel-Forschung [Pharmaceutical Agent Research] (Drug Res.), 24 (1974) 896-900].
The process for the production of the starting materials with general formula II: 
which are required for the production of the compounds according to the invention with general formula I, is described in EP 0 411 733 A2 and DE 43 32 283 A1:
For the production of the compounds with general formula II, for example, a compound that is indicated with general formula III below can be used, whereby R3xe2x80x2, R4xe2x80x2, R6xe2x80x2, R7xe2x80x2 and R8xe2x80x2 have the meaning of corresponding radicals R3xe2x80x2, R4xe2x80x2, R6, R7 or R8 that are indicated in EP 0 411 733 A2 in formula II: 
and in this connection, the latter are converted under acid treatment in a water-miscible solvent, optionally while being heated, in a compound in which the radicals are reacted in 3-position to form a 3-oxo group, and a xcex944,5-double bond in the steroid skeleton is formed by release of the hydroxy group in 5xcex1-position. In this connection, more detailed information is contained in EP 0 411 733 A2, which is incorporated herewith in this application as a disclosure. The processes that are used for the production of compounds with general formula III, which depend on the ultimately desired substituents of the compounds according to the invention, are also indicated in more detail in EP 0 411 733 A2. Therefore, the disclosure that is related thereto in this document is also incorporated in this application. The corresponding data in DE 43 32 283 A1 for the production of compounds with general formula II are also incorporated as disclosures in this application.
To form the benzaldoxime group and thus to produce the compounds of general formula I according to the invention, it is proposed in a way according to the invention to react the compound with general formula II that is obtained by introducing the fluorinated alkyl group in 17xcex2-position with a salt of a hydroxylamine in a basic solvent, such that a 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroid is produced, in which R1 is hydrogen, and then optionally to esterify this compound, to etherify it or to convert it into a corresponding carbamate, carboxylic acid derivative or thiocarboxylic acid derivative. The additional radicals R2 and R3 in this general formula have the meanings that are further indicated above. The salt of the hydroxylamine in this case is preferably a hydrochloride or hydrosulfate. The basic solvent is preferably pyridine.
For the production of the compounds according to the invention, the compound with general formula II can be reacted in an alternative embodiment of the invention also with a compound with general formula NH2xe2x80x94Oxe2x80x94R1, in which R1 has the previously-mentioned meaning. Also, in this connection, reference is made to the corresponding description in DE 43 32 283 A1, which is incorporated herewith in the disclosure of this application.
The methods for the in-vitro tests and the in-vivo tests with the compounds according to the invention can be found in EP 0 411 733 A2 and DE 43 32 283 A1:
The 17xcex1-fluoroalkyl-11xcex2-benzaldoxime steroids according to the invention are bonded to the progesterone receptor (cf. Table 1) and in comparison to RU 486 (11xcex2-(4-dimethylaminophenyl)-17xcex2-hydroxy-17xcex1-propinyl-estra-4,9-dien-3-one) generally have a considerably reduced antiglucocorticoidal action, detected by the reduced glucocorticoid receptor bond in vitro (cf. Table 1).
The compounds according to the invention are suitable for postmenopausal substitution therapy and for treatment of gynecological diseases, such as hysteromyomas, as well as for treatment of dysmenorrhoic symptoms.
Subjects of this invention are also pharmaceutical substances (pharmaceutical preparations) for oral, rectal, subcutaneous, intravenous or intramuscular use, which together with commonly used vehicles and optionally diluents contain at least one compound with general formula I as active ingredient.
Pharmaceutical agents according to the invention are produced with commonly used solid or liquid vehicles and/or diluents and the common generally used adjuvants corresponding to the desired type of administration in a suitable dosage and in a way that is known in the art. In a preferred oral dispensing form, preferably tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions are also prepared as a depot form.
In addition, parenteral dosage forms, such as injection solutions or else suppositories, are taken into consideration.
Dosage forms as tablets can be produced, for example, by mixing active ingredient with known adjuvants, such as dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosives, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents that can achieve a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tables analogously can be prepared by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example polyvinyl pyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The shell of the coated tablet in this case can also consist of several layers, whereby, for example, the above-mentioned adjuvants are used.
The solutions or suspensions with the active ingredient according to the invention can be mixed for improving the taste with substances, such as saccharine, cyclamate or sugar, and/or with flavoring substances, such as vanilla or orange extract. In addition, they can be mixed with suspension adjuvants, such as sodium carboxymethyl cellulose, or preservatives, such as p-hydroxybenzoic acid.
The capsules can be produced by mixing pharmaceutical substance with vehicles, such as lactose or sorbitol, which then are introduced into the capsules.
Suppositories can preferably be produced by mixing active ingredient with suitable carrier materials, such as neutral fats or polyethylene glycols or derivatives thereof.
The galenical preparation contains the active ingredients in an amount of 1-100 mg, whereby when used in humans, amounts in the range of 1-600 mg per day are required.
This invention is explained, but not limited, by the subsequent examples.